Multiple Myeloma Disease Background

Introduction

Multiple myeloma is a bone marrow disease characterized by the presence of malignant plasma cells, and abnormal serum and/or urine immunoglobulin (Ig) secondary to clonal plasma cell expansion.

Epidemiology

Multiple myeloma accounts for 1-2% of all cancers worldwide. It is the second most frequent hematologic malignancy in the United States, with a rapidly increasing incidence rate in Asia. The median age of onset is 69 years old. 

Pathophysiology

Multiple myeloma is always preceded by a premalignant stage, monoclonal gammopathy of undetermined significance (MGUS), although only 10% of patients with newly diagnosed multiple myeloma have a documented history of pre-existing monoclonal gammopathy of undetermined significance since patients with monoclonal gammopathy of undetermined significance are asymptomatic.  

The rate of progression of monoclonal gammopathy of undetermined significance to multiple myeloma is 1% per year. Non-IgM immunoglobulin monoclonal gammopathy of undetermined significance (non-IgM MGUS) makes up 80% of premalignant multiple myeloma. Light-chain Ig monoclonal gammopathy of undetermined significance makes up 20% of premalignant multiple myeloma. IgM immunoglobulin MGUS usually develops into Waldenström macroglobulinemia but may rarely evolve into multiple myeloma (IgM myeloma).

Etiology

There are 2 processes being considered to be the root cause of multiple myeloma, the premalignant stage or the appearance of monoclonal gammopathy of undetermined significance (MGUS) and the disease progression from the monoclonal gammopathy of undetermined significance to multiple myeloma.  

Premalignant Stage: Appearance of Monoclonal Gammopathy of Undetermined Significance (MGUS)  

The premalignant stage is brought about by cytogenetic abnormalities and/or abnormal cellular response to an antigenic stimulus. Malignant transformation of plasma cells leads to the production of monoclonal paraprotein (M-protein) composed of single heavy and light chain immunoglobulins. Abnormal immunoglobulins include IgG, IgM, IgA, and rarely IgE and IgD; light chain proteins κ and λ are also seen. These immunoglobulins cause hyperviscosity and end-organ damage.  

The chromosomal aberrations identified with multiple myeloma include del17p13, IgH gene rearrangement at 14q32, 14q32 translocations (t[11;14][q13;q32], t[4;14][p16;q32], t[14;16][q32;q23], t[14;20][q32;q12]) and chromosome 1 abnormalities. These aberrations lead to the development of plasma cell clones.  

An antigenic stimulus when interpreted by cells (eg toll-like receptors [TLRs] on myeloma cells, interleukin-6 (IL-6)] abnormally causes an increase in plasma cells, thereby causing chromosomal changes leading to plasma cell clones and abnormally produced immunoglobulins.

Disease Progression from MGUS to Multiple Myeloma  

Triggering factors that contribute to the development of monoclonal gammopathy of undetermined significance into multiple myeloma include secondary cytogenetic aberrations (secondary IgH translocation, Ras mutations, activation of the NF κ B pathway), abnormalities in the cell cycle pathway, interrupted apoptosis, and various factors affecting the bone marrow. 

Risk Factors

The risk factors for the development of multiple myeloma include age (increases risk), immunosuppression, environmental exposures, gender (more common in men), and occupational exposure to toxic substances such as radiation, solvents, herbicides, and insecticides. 

Classification

Smoldering (Asymptomatic) Multiple Myeloma  

Smoldering multiple myeloma is also called smouldering or indolent myeloma. It is the more advanced premalignant stage next to monoclonal gammopathy of undetermined significance and before progression to active multiple myeloma.    

Patients present symptom-free and without any end-organ impairment. It is usually diagnosed based on laboratory findings. The progression rate is 10% per year within the first 5 years after confirmed diagnosis.  

Active (Symptomatic) Multiple Myeloma  

Active multiple myeloma is the symptomatic form of multiple myeloma with additional biomarker-confirmed events. Patients present with bone pain, nonspecific constitutional symptoms, and other symptoms related to end-organ damage.